KR20040023740A - Polysaccharide-Containing Compositions and Use Thereof - Google Patents

Abstract

The present invention aims to provide pharmaceuticals, eye drops, foods, cosmetics, bathroom products, etc., having a new texture and / or function by adjusting a composition in a low viscosity liquid state while containing a high concentration of polysaccharides. After heating a high concentration of polysaccharides, for example, agar, in a water-containing liquid and cooling with application of shearing force, a composition in a low-viscosity liquid state can be obtained, and the drug can be provided. The composition which can be used as an aqueous pharmaceutical composition base material which does not produce gelatinization by the change of the environmental temperature during storage, and is difficult to flow easily to apply | coat, can be provided. In addition, eye drops formulated with agar have an effect of improving intraocular performance of the drug. In addition, when the particulate agar is blended into the eye drop, it can be maintained at a low viscosity, so that the injection of the liquid is good and the feeling at the time of eye drop is also excellent.

Description

Polysaccharide-Containing Compositions and Use Thereof

Various gelling agents and thickeners are used in the fields of medicine, food, cosmetics, bathroom products, and the like, and gel and sol products are commercially available. Although safe and good images of natural polysaccharides and proteins are used in these fields, there is a need for reversible control of sol, gel texture, stability, or gelation temperature or sol / gel state.

As a document showing that a polysaccharide is a hydrogel, which is first pulverized using a shearing force, and has fluidity, Japanese Patent Application Laid-Open No. 2002-514395, Japanese Patent Application Laid-Open No. 2000-239147, etc., but the viscosity of the composition obtained High and lack of uniformity of fluid.

Other well-known documents of low viscosity and fluidity-containing polysaccharide-containing compositions are described, for example, in EP 432835, wherein the microgels of polysaccharides are subjected to a shearing process when cooling from a temperature above the gelation temperature of the polysaccharide to below the gelation temperature. Fluid compositions comprising and methods of making the same are described.

Moreover, Japanese Patent No. 2,513,506, Unexamined-Japanese-Patent No. 2000-119116, etc. are known as an example of the low viscosity, fluidity-containing polysaccharide composition manufactured by the same manufacturing method. In this series of fluid compositions, and methods of preparation, the higher the shear force (shear rate), the lower the viscosity of the fluid as outlined in International Jornal of Biological Macromolecules, 26 (1999), p 255-261, FIG. Obtained.

In addition, an aqueous pharmaceutical composition that efficiently releases an active ingredient to a mammal in need of treatment, some aqueous pharmaceutical compositions that are liquid at room temperature or lower, and semisolid or gelated at the body temperature of the mammal are disclosed. There is a problem that the gelation of the solution occurs due to the rise of the environmental temperature.

For example, US Pat. No. 4,188,373 discloses a thermogelled aqueous pharmaceutical composition using Pluronic (trade name PLURONIC), while US Pat. No. 4,47,8,822 describes a drug release system using a thermogelled aqueous pharmaceutical composition. It is.

However, in the case of skin creams for the purpose of blocking sun, etc., there are some types such as lotion (liquid), gel, and ointment, but the closer to the liquid, the easier it is to be applied uniformly, while the liquid is flowed. There is a flaw that is easy to fall.

Moreover, since agar contains plant fiber, the effect of improving bowel movement is expected. However, it has been desired to develop a drinkable food product which is easily gelled and consumed at a concentration of 0.1% by weight or more.

On the other hand, as a method of treating eye diseases, a method of administering eye drops is common. The therapeutic effect of eye diseases caused by the topical administration depends, of course, on the efficacy of the drug itself, but how to effectively transfer the drug to the guidance in order to fully exhibit the effect is an important problem.

Various studies have been made to improve the intraocular performance of drugs, for example, by using carboxyvinyl polymer (CVP) as a base to increase the viscosity of eye drops and lengthen the residence time of drugs on the inner surface, There is a technique (Japanese Patent Publication No. 60-56684) that measures the sustained-release effect and improves the guide performance. This technique utilizes the properties of CVP, that is, the property of dramatically increasing the viscosity of eye drops even at a small amount of addition.

In the case of ophthalmic ointment, the above technique can be preferably used, but in the case of eye drops, it is necessary to apply eye drops in the form of droplets, so that eye drops can be applied in the form of droplets and excellent drug guidance can be achieved. I was asking. For example, the study of CVP showing Newtonian viscosity that can be instilled in the state of droplets (Japanese Patent No. 2873530), and the study of a polymer that gels rapidly when it comes into contact with the leakage after instillation in the form of droplets (Japanese Patent No. 2814637). And polysaccharides (Japanese Patent Laid-Open No. 6-67853) which cause liquid-gel phase transitions.

In general, polysaccharides represented by agar contain at least 0.1% by weight and gelate when cooled at a temperature above the gel transition temperature of room temperature or more, and cannot be used as a liquid composition with fluidity at room temperature. Thus, a composition containing a high concentration of polysaccharides represented by agar, in a low viscosity liquid state at room temperature, and providing pharmaceuticals, foods, cosmetics, bathroom products, and the like, which have no texture and / or function Let's make it a task. Moreover, when using it as a food for improving bowel movement, it is a subject to provide it as a liquid food which is not a jelly phase but is easier to take.

In addition, as for ophthalmic drugs, it is difficult to obtain a mechanism for eye drops, which is satisfactory in the prior art, and it is desired to develop a new mechanism capable of improving intraocular drug delivery and instilling droplets. .

The important problem in the development of this new mechanism is

1) There is no problem in safety,

2) raw materials can be easily obtained,

3) easy to process and handle;

4) can be easily dispensed in the state of droplets,

5) Excellent usability (feeling when eye drops),

6) Has excellent intraocular performance of the drug.

The present invention relates to a polysaccharide-containing composition which contains a high concentration of polysaccharides and exhibits low viscosity properties. Moreover, it is related with the composition which can lengthen holding time of the chemical | medical agent, pigment, coating material, etc. which contain by using the composition of this invention. Moreover, this invention relates to the eye drop which improved the intraocular transition property of a drug by mix | blending agar. In particular, when a particulate agar is used as a base for eye drops, eye drops having excellent characteristics can be obtained.

1 shows an optical micrograph of the agar solution prepared in Production Example 1. FIG.

2 shows the relationship between the viscosity and the stirring speed (corresponding to the shearing speed) in Production Examples 4 to 9 and Production Examples 26 to 30. FIG.

3 is a graph showing the results of measuring the concentration of fluorescein in the cornea at each time after injecting eye drops of Test Example 10, Test Example 12, and Comparative Test Example 2 (control) into rabbits. The vertical axis represents fluorescein concentration (ng / mL) in the cornea and the horizontal axis represents time (hr).

Fig. 4 is a graph showing the results of measuring the concentration of fluorescein in waterproofing after each eye drop of Test Example 10, Test Example 12, and Comparative Test Example 2 (Control) to the rabbit. The vertical axis represents the fluorescein concentration (ng / mL) in the waterproofing, and the horizontal axis represents time (hr).

Fig. 5 is a graph showing the results of measuring pupil reduction values by pilocarpin at each time after eye drops of Test Example 20 and Comparative Test Example 3 (control group) were applied to rabbits. The vertical axis represents pupil reduction value (mm) by pilocarpin, and the horizontal axis represents time (hr).

Best Mode for Carrying Out the Invention

Although an Example is given to the following and this invention is demonstrated, these examples are for understanding this invention better, and do not limit the scope of the present invention.

(1) Preparation and evaluation test of agar-containing composition (agar solution)

① Weight average molecular weight measurement

According to the following measurement conditions, the weight average molecular weight of the agar was measured.

Measuring conditions

A. Apparatus: Gel Permeation Chromatograph

(M510 high pressure pump, U6 universal injector)

B. Data Processing: Toray Research Center (TRC) Manufacturing CPC Data Processing System

C. Column: TSK-gel-GMPWXL (inside diameter 7.8 mm / length 30 cm) (2 pieces) (Tosoh Corporation make)

D. Solvent: 0.1 M-NaNO ₃ / Distilled Water

E. flow rate: 1.0 ml / min

F. Column temperature: 50 degreeC (column thermostat: the Tosoh Corporation make)

G. Sample concentration: 0.1% (wt / vol)

Solubility: Visually confirm that the measurement solvent is dissolved

Filtration: 0.45 μm- Meishorizu disk (Maishoridisuku) W-13-5 (manufactured by Tosoh Corporation)

H. Injection volume: 200 μl

I. Detector: Differential Refractive Index Detector, R-401 (manufactured by Tosoh Corporation)

J. Molecular weight calibration: 14 kinds of pullulan (manufactured by Showa Denko)

The weight average molecular weight of the agar measured under the above conditions is shown in Table 1 below. In addition, all the agars of Table 1 are manufactured by Shokkin High School.

Agar Weight average molecular weight AX-30 89400 AX-100 125000 AX-200 153000 BX-30 125000 BX-100 202000 BX-200 273000 UP-6 221000 M-9 449800 PS-7 374000 Agarose (Agarose DNA Grade) 299000

② How to measure particle size

After preparing the agar-containing compositions, the particle size of each composition was measured by the optical microscope (OPTIPHOTO-2 manufactured by Nikon Corporation) to determine the maximum particle diameter of the particles.

③ Viscosity Measurement Method

After preparing an agar-containing composition, the viscosity of each composition was measured on the conditions of 20 degreeC and 60 rpm with the Brookfield viscometer (rotor No. 2).

④ Manufacturing method

<Preparation A>

Place agar in a 500 ml flask and add distilled water to make 500 g. The mixture is heated to dissolve at about 100 ° C. and then cooled to 20 ° C. with stirring at 1500 rpm in a magnetic stirrer.

<Manufacturing B>

Agar is placed in a 500 ml flask and distilled water is added to make 500 g. The mixture is heated in a microwave to dissolve at high temperature, and then cooled to 20 ° C. while stirring at 1500 rpm in a magnetic stirrer. Thereafter, 13 g of glycerine was added and stirred for 30 minutes at 1500 rpm in a magnetic stirrer at 20 ° C.

<Manufacturing C>

The agar is placed in a 500 ml four-necked flask with a teflon stirring blade, and distilled water is added to make 500 g. The mixture is heated with an oil bath to dissolve at about 100 ° C. and then cooled to 20 ° C. with stirring at 700 rpm.

<Manufacturing D>

Agar was prepared in a 500 ml four-necked flask with a Teflon stirring blade, and distilled water was added to make 500 g. The mixture is heated with an oil bath to dissolve at about 100 ° C. and then cooled to 80 ° C. while stirring at 700 rpm using a stirring blade. The solution is transferred to a stainless steel production vessel, and then cooled to 20 ° C while stirring with a homo mixer (T. K. HOMO MIXER manufactured by Tokushu KKK).

⑤ Production example

The manufacture example of the agar containing composition (agar solution) of this invention is shown below. The agar solutions obtained in Production Examples 1 to 25 each had a viscosity of 700 mPa · s or less, and as a result of optical microscopic observation, particulate agar was present. In addition, the optical micrograph of the agar solution of the manufacture example 18 is shown in FIG.

<Manufacture example 1>

Agar-containing compositions (agar solutions) were prepared in Production Method A using 2.5 g (0.5 wt%) of agar (UP-6). This agar solution was opaque, had a viscosity of 93 mPa · s, and had a particle diameter of less than 10 m.

<Manufacture example 2>

Agar solution was prepared in Preparation A using 2.5 g (0.5 wt%) of agar (AX-30). This agar solution was cloudy, had a viscosity of 40 mPa · s, and had a particle diameter of less than 10 µm.

<Manufacture example 3>

Agar solution was prepared in Preparation B using 2.5 g (0.5 wt%) of agar (AX-30). This agar solution was cloudy and had a viscosity of 31 mPa · s.

<Manufacture example 4>

Using agar (AX-30), the rotation speed of the homo mixer was set to 3000 rpm and agar solution was prepared in Preparation D. This agar solution was pale yellow pale, had a viscosity of 32 mPa · s and a particle diameter of less than 10 µm.

Production Example 5

Using agar (AX-30), the rotation speed of the homo mixer was set to 4000 rpm and agar solution was prepared by Preparation D. This agar solution was pale yellow pale, had a viscosity of 51 mPa · s and had a particle diameter of less than 10 m.

<Manufacture example 6>

Using agar (AX-30), the rotation speed of the homo mixer was set to 5000 rpm and agar solution was prepared in Preparation D. This agar solution was pale yellow pale, had a viscosity of 67 mPa · s and had a particle diameter of less than 10 m.

<Manufacture example 7>

Using agar (AX-30), the rotation speed of the homo mixer was set to 6000 rpm, and agar solution was prepared by Production Method D. This agar solution was pale yellow pale, its viscosity was 81 mPa · s, and its particle size was less than 10 m.

<Manufacture example 8>

Using agar (AX-30), the speed of the homo mixer was set to 8000 rpm, and agar solution was prepared in Preparation D. This agar solution was pale yellow white, its viscosity was 94 mPa · s, and the particle size was less than 10 µm.

<Manufacture example 9>

Using agar (AX-30), the rotation speed of the homo mixer was set to 10000 rpm and agar solution was prepared by Preparation D. This agar solution was pale yellow pale, had a viscosity of 144 mPa · s and had a particle diameter of less than 10 m.

Production Example 10

Using agar 2.5 g (0.5% by weight) of agar (UP-6), the rotation speed of the homo mixer was set to 6000 rpm, and agar solution was prepared by Preparation D. This agar solution was cloudy and had a viscosity of 403 mPa · s. In addition, the particle diameter was less than 10 micrometers.

Production Example 11

Using agar (M-9) 2.5 g (0.5 wt%), the speed of the homomixer was set to 6000 rpm, and agar solution was prepared by Preparation D. This agar solution was cloudy and had a viscosity of 200 mPa · s. In addition, the particle diameter was less than 10 micrometers.

Production Example 12

Using 2.5 g (0.5 wt%) of agar (AX-30), the speed of the homomixer was set to 6000 rpm, and agar solution was prepared by Preparation D. This agar solution was pale yellow pale, and the viscosity was 20 mPa · s. In addition, the particle diameter was less than 10 micrometers.

Production Example 13

Using agar (AX-100) 2.5 g (0. 5% by weight), the rotation speed of the homomixer was set to 6000 rpm, and agar solution was prepared in Preparation D. This agar solution was pale yellow pale, and had a viscosity of 62 mPa · s. In addition, the particle diameter was less than 10 micrometers.

Production Example 14

Using agar (AX-200) 2.5 g (0.5% by weight), the speed of the homo mixer was set to 6,000 rpm, and agar solution was prepared by Preparation D. This agar solution was pale yellow pale, and had a viscosity of 62 mPa · s. In addition, the particle diameter was less than 10 micrometers.

Production Example 15

Using 2.5 g (0.5 wt%) of agar (BX-30), the rotation speed of the homomixer was set to 6000 rpm, and agar solution was prepared by Preparation D. This agar solution was pale yellow pale, and the viscosity was 96 mPa · s. In addition, the particle diameter was less than 10 micrometers.

Production Example 16

Using agar (agarose: agarose DNA grade 2.5 g (0.5% by weight)), the agitation speed of the homo mixer was set to 6000 rpm and agar solution was prepared by Preparation D. This agar solution was cloudy, and the viscosity was 158. mPa · s, and the particle size was less than 10 m.

Production Example 17

Using 2.5 g (0.5 wt.%) Of agar (PS-7), the agitation speed of the homo mixer was set to 6000 rpm and agar solution was prepared by Preparation D. This agar solution was cloudy and had a viscosity of 190 mPa · s. In addition, the particle diameter was less than 10 micrometers.

Production Example 18

Agar solution was prepared in Preparation A using 5.0 g (1.0 wt%) of agar (UP-6). This agar solution was cloudy, had a viscosity of 384 mPa · s and had a particle diameter of less than 20 µm.

Production Example 19

Agar solution was manufactured by the manufacturing method A using 5.0 g (1.0 weight%) of agar (product name BA-10) by a Funakoshi company. This agar solution was cloudy, had a viscosity of 297 mPa · s and had a particle diameter of less than 20 µm.

Production Example 20

Agar solution was prepared in Preparation A using 2.5 g (0.5 wt%) of agar (AX-100). This agar solution was cloudy, had a viscosity of 133 mPa · s and had a particle diameter of less than 10 µm.

Production Example 21

Agar solution was prepared in Preparation A using 2.5 g (0.5 wt%) of agar (AX-200). This agar solution was cloudy, had a viscosity of 133 mPa · s and had a particle diameter of less than 10 µm.

Production Example 22

Agar solution was prepared in Preparation A using 2.5 g (0.5 wt%) of agar (BX-30). This agar solution was cloudy, had a viscosity of 41 mPa · s and a particle diameter of less than 10 µm.

Production Example 23

Agar solution was prepared by Preparation C using 2.5 g (0.5 wt.%) Of agar (BX-30). This agar solution was cloudy, had a viscosity of 142 mPa · s and had a particle diameter of less than 10 µm.

<Manufacture example 24>

Agar solution was prepared following Preparation A using 2.5 g (0.5 wt.%) Of agar (PS-7). This agar solution was cloudy, had a viscosity of 87 mPa · s and had a particle diameter of less than 10 µm.

Production Example 25

Agar solution was prepared in Preparation A using 2.5 g (0.5 wt%) of agar (M-9). This agar solution was cloudy, had a viscosity of 106 mPa · s and a particle diameter of less than 10 µm.

Production Example 26

An aqueous solution of gellan gum was prepared in the same manner as in Preparation Example 4 except that gellan gum (GP-10 manufactured by Inasho Kogyo Co., Ltd.) was used in place of agar. The solution was transparent, the viscosity was 137 mPa · s, and the particle diameter was less than 10 μm.

Production Example 27

A gellan gum aqueous solution was prepared in the same manner as in Preparation Example 6 except that gellan gum (GP-10, manufactured by Inasho Kogyo Co., Ltd.) was used in place of agar. The solution was transparent, the viscosity was 160 mPa · s, and the particle diameter was less than 10 μm.

Production Example 28

A gellan gum aqueous solution was prepared in the same manner as in Preparation Example 7 except that gellan gum (GP-10, manufactured by Inasho Kogyo Co., Ltd.) was used in place of agar. The solution was transparent, the viscosity was 150 mPa · s, and the particle diameter was less than 10 μm.

Production Example 29

A gellan gum solution was prepared in the same manner as in Preparation Example 8, except that gellan gum (GP-10, manufactured by Inasho Kogyo Co., Ltd.) was used in place of agar. The solution was transparent, the viscosity was 148 mPa · s, and the particle diameter was less than 10 μm.

Production Example 30

A gellan gum solution was prepared in the same manner as in Preparation Example 9, except that gellan gum (GP-10 manufactured by Inasho Kogyo Co., Ltd.) was used instead of agar. The solution was transparent, the viscosity was 158 mPa · s, and the particle diameter was less than 10 µm.

Production Example 31

Instead of agar, gellan gum (GP-10 manufactured by Inasho Kogyo Co., Ltd.) was used to set the rotation speed of the homomixer to 6000 rpm, and an aqueous gellan gum solution was prepared according to Production Process D. The solution was transparent and the viscosity was 103 mPa · s. In addition, the particle diameter was less than 10 micrometers.

<Comparative Production Example 1>

2.5 g (0.5% by weight) of agar (UP-6) was added to a 500 mL flask, and 500 g of distilled water was added thereto to disperse, and once dissolved at a high temperature, the liquid was cooled to 20 ° C without stirring. The prepared 0.5 wt% agar gel was filtered through a sieve of pore size φ 1 mm. The finely ground gel had a viscosity of 900 mPa · s.

<Comparative Production Example 2>

Agar solution was prepared in Preparation A using 0.25 g (0.05 wt.%) Of agar (AX-30). The viscosity of this agar solution was 14 mPa · s.

<Comparative Production Example 3>

Agar solution was manufactured by the manufacturing method A using 2.5 g (0.5 weight%) of agar (AX-30) except having made the rotation speed of a magnetic stirrer into 500 rpm. This agar solution became a mixture of a gel and a solution and could not measure viscosity.

⑥ Applicability Evaluation

The ease of application | coating and the state after application | coating when each solution of manufacture examples 1-3 and the comparative manufacture examples 1-3 were applied to skin were evaluated. These results are shown in Table 2 below.

Applicability State after application Preparation Example 1 Easy to apply Not flowing well Preparation Example 2 Easy to apply Not flowing well Preparation Example 3 Easy to apply Not flowing well Comparative Production Example 1 Difficult to apply Not flowing well Comparative Production Example 2 Easy to apply Dripping soon Comparative Production Example 3 Difficult to apply Not flowing well

According to the said Table 2, each solution of the manufacture examples 1-3 has the characteristic which it is easy to apply | coat and does not flow down. On the other hand, although each solution of the comparative manufacture examples 1 and 3 does not flow, it is difficult to apply | coat, and the solution of the comparative manufacture example 2 is easy to apply | coat, but there existed a fault which flows down immediately.

⑦ Relationship between viscosity and stirring speed

The relationship between the viscosity and the stirring speed (corresponding to the shearing speed) in Production Examples 4 to 9 and Production Examples 26 to 30 is shown in FIG. 2. As apparent from Fig. 2, in Production Examples 4 to 9, the viscosity was confirmed to increase as the stirring speed increased, whereas in Production Examples 26 to 30, the viscosity was almost constant even if the stirring speed was increased.

⑧ Evaluation test for thickening rate

To 50 g of the agar solution prepared in Production Examples 10 to 17 and Production Example 31, 0.025 g of sodium fluorescein and 1.3 g of glycerin were added thereto, and the mixture was sufficiently mixed, and the pH was adjusted to 7. The viscosity of this agar solution was measured on the conditions of 20 degreeC and 60 rpm with the Brookfield viscometer (rotor No.2). This viscosity value is set to Y.

Next, NaCl was added to the agar solution so as to have a concentration of 0.9% by weight, and the mixture was sufficiently mixed. The viscosity of this agar solution was measured on the conditions of 20 degreeC and 60 rpm with the Brookfield viscometer (rotor No. 2). Let this viscosity value be Z.

The thickening rate X was computed based on the following formula.

X = Z / Y

In addition, each solution was applied to the forearm skin of a human, and the ease of application and the state after application were compared. These results are shown in Table 3 below.

From Table 3, in Test Examples 1 to 8, it is easy to apply, has a suitable viscosity on the skin surface, and further shows a characteristic that is difficult to flow down. On the other hand, it is easy to apply in Test Example 9 and Comparative Test Example 1, but after applying in Test Example 9, as a result of excessively sharp thickening, gelation occurs on the skin surface, causing discomfort, and in Comparative Test Example 1, defects that flow down immediately after application There was this.

(2) guidance performance examination

A. Guided transition test by fluorescence photometry

(i) Manufacturing method of eye drop

To agar solutions (100 g each) prepared in Production Examples 1, 2 and 18 to 25, 0.05 g and 2.6 g of sodium fluorescein and concentrated glycerin were respectively added. Subsequently, this was stirred for 2 minutes with a hybrid mixer (HM-500, manufactured by Keyence Co., Ltd.) to obtain each eye drop. Furthermore, sodium hydroxide or dilute hydrochloric acid was added to each eye drop to adjust the pH to 7.0 (± 0.5). Using the E-type viscometer Rotovisco CV 20 (HAAKE Co., Ltd.), the value when the shear rate was 100 s ⁻¹ at a measurement temperature of 25 ° C. was measured to be a viscosity. In addition, the particle diameter of the agar measured the maximum particle diameter of particle | grains using the optical microscope (OPTIPHOTO-2 by Nikon Corporation). In addition, a comparative eye drop (Comparative Test Example 2) was obtained by performing the same operation using sterile purified water in place of the agar solution as a control.

(ii) Administration method and measurement method

After each eye drop obtained by the above production method was applied to the eyes of male Japanese white rabbits, the concentration of fluorescein in the cornea and water after 1, 2, 3, 4, 6 and 8 hours was measured using a fluorescence spectrophotometer. (In addition, the average value was computed by measuring in 4 rows, respectively with each test eyedrop and a comparative eyedrop).

The AUC (area below the concentration curve) was calculated from the measured value of the fluorescein concentration, and the AUC ratio of each eye drop to the comparative eye drop was determined by the following equation. These results are shown in Table 4 below. In addition, the fluorescein concentrations in the cornea and waterproofing are shown in FIGS. 3 and 4.

In addition, except that a CVP solution (1.0%) was used in place of the agar solution, eye drops were prepared in the same manner as in the above production method, but eye drops containing CVP were very high in viscosity (1139 mPa · s) and thus could not be dispensed. .

B. Guided Transition Testing with Phylocarpine

(i) Manufacturing method of eye drop

To the agar solution (100 g) prepared in Preparation Example 1, 1.0 g and 2.6 g of hydrochloric acid hydrochloride and concentrated glycerin were added, respectively. Subsequently, this solution was stirred with a magnetic stirrer to obtain a test eye drop. Furthermore, sodium hydroxide or dilute hydrochloric acid was added to the eye drop, and the pH was adjusted to 7.0. The viscosity (25 degreeC) was measured with the E-type viscosity meter. In addition, a comparative eye drop (Comparative Test Example 3) was obtained by performing the same operation using sterile purified water in place of the agar solution (Preparation Example 1) as a control.

(ii) Administration method and measurement method

Each eye drop obtained by the above production method was applied to the eyes of male Japanese white rabbits, and then the pupil diameters of 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5 and 3 hours were measured. The value obtained by subtracting the pupil diameter at the time of each measurement from the pupil diameter before eye drop was defined as the pupil reduction value (in addition, the average value was calculated by measuring six rows with the eye drop and the comparative eye drop). In addition, AUC (area under the pharmacological effect-time curve) was calculated from the obtained pupil reduction value. These results are shown in Table 5 below.

(3) Formulation Example

Examples of preparations of representative eye drops and ear drops used in the present invention are shown below.

<Prescription 1>

Pylocarpine hydrochloride and concentrated glycerin were added to the agar solution (100 g) prepared in Preparation Example 18, followed by stirring for 2 minutes with a hybrid mixer (HM-500, manufactured by Keyence), and then diluted with 0.1 N sodium hydroxide or 0.1 N diluted. Hydrochloric acid was added to adjust the pH to 7.0 to prepare an eye drop.

In 100 g

Agar (UP-6) 1.0 g

Phylocarpine hydrochloride1.0 g

Dark glycerin 2.6 g

Sodium Hydroxide

Hydrochloric acid

Sterile purified water

<Prescription 2>

Pranopropene and concentrated glycerin were added to the agar solution (100 g) prepared in Preparation Example 1, followed by stirring for 2 minutes with a hybrid mixer (HM-500, manufactured by Kyens), followed by 0.1 N sodium hydroxide or 0.1 N dilute hydrochloric acid. The pH was adjusted to 7.0 to prepare an eye drop.

In 100 g

Agar (UP-6) 0.5 g

Pranopropene0.1 g

Dark glycerin 2.6 g

Sodium Hydroxide

Hydrochloric acid

Sterile purified water

By preparing agar solutions of various concentrations and performing the same operation as in Formulations 1 and 2, eye drops containing agar of a desired concentration can be produced.

<Prescription 3>

A ear drops solution was prepared by the following prescription.

Gatifloxacin0.5 g

0.1 g sodium edetate

Sodium chloride0.9 g

Agar solution of Preparation Example 7 70.0 g

Purified water 28.5 g

These components were stirred and mixed until uniform, and the prepared solution was adjusted to pH 7.0 using an appropriate amount of hydrochloric acid or sodium hydroxide. Although the obtained viscosity solution was low viscosity and was extremely excellent in electrodeposition property, the flow of the liquid after a point did not generate | occur | produce.

Industrial availability

According to the present invention, by heating a polysaccharide in a water-containing liquid and cooling with a shearing force, a composition containing a high concentration of polysaccharide in a low viscosity liquid state can be prepared, and has a texture and / or function that has never been achieved. It is possible to provide medicines, food, cosmetics and bathroom products. In addition, when the polysaccharide is used as a food for improving bowel movement, it is possible to provide it as a liquid food that is easier to take, rather than a jelly phase.

From the results of the guided shift test by fluorescence photometry (Table 4, FIG. 3 and FIG. 4), the eye drop of the present invention has a viscosity suitable for the eye drop, and when the eye drop is applied, fluorescein migrates to the cornea and the waterproof, and the high concentration (control group) 3 to 6 times). In addition, when the eye drops of the present invention were applied from the results of the intraocular transition test using the ophthalmic drug pilocarpine (Table 5 and FIG. 5), the AUC (the area under the pharmacological effect-time curve) of the pilocarpine was not less than twice that of the control group. Increase. As described above, the eye drop containing the agar of the present invention has an effect of improving the intraocular performance of the drug and can be kept at a low viscosity, so that the liquid injection of the eye drop is good, and the amount of the eye drop is constant so that the feeling of use during eye drop is constant. Is also excellent.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, as a result, after heating a polysaccharide, for example, agar in a water containing liquid, and cooling it under stress, such as a shear force, it is surprisingly 0.1% by weight of the polysaccharide represented by agar. It discovered that it can manufacture the low viscosity liquid water containing composition, including at the above concentration, and came to this invention.

That is, 1st invention contains the "polysaccharide of 0.1-30 weight%, and the viscosity measured on condition of 20 degreeC and 60 rpm by the B-type viscometer (rotor No. 2) is 700 mPa * s or less, The polysaccharide characterized by the above-mentioned. Containing composition. "And" The manufacturing method of the said composition characterized by cooling while heating a polysaccharide in a water containing liquid, and applying a shear force. " Moreover, as a result of earnestly examining, it is related with the polysaccharide containing composition and manufacturing method of Claim 1, so that the viscosity of the polysaccharide containing composition obtained will become so high that a shear force (shear rate) is large. By using such "polysaccharide-containing compositions" and "thickness compositions", it has become possible to provide completely new "medicines", "guided performance enhancing agents", "food", "cosmetics".

In addition, the present inventors have focused on agar which is widely used in foods and the like. As a result of earnestly examining in order to solve the above-mentioned problems in ophthalmic applications, the present inventors heat-dissolve agar in an aqueous solution and then cool it while applying stress to agar of high concentration. It discovered that it was liquid and was able to manufacture the particulate agar of a desired viscosity. In general, agar containing at least 0.1% by weight of agar gels at room temperature. However, even when the particulate agar contains a high concentration of agar, the agar retains its liquidity and does not have a high viscosity. It has been found that when the particulate agar is used as a base for eyedrops, excellent intraocular performance of the drug can be exhibited, and new "eyedrops" and "intraocular performance enhancers" can be provided.

That is, 2nd invention is "eye drop which improved the intraocular performance of a drug by mix | blending agar." In particular, when a particulate agar is used as a base for eye drops, eye drops having excellent characteristics are obtained. In addition, the present invention is an "information performance enhancing agent for drugs, which is characterized by using agar as a base".

1st invention contains the "agar containing 0.1-30 weight% polysaccharide, and the viscosity measured on condition of 20 degreeC and 60 rpm by the B-type viscosity meter (rotor No. 2) is 700 mPa * s or less, The agar containing composition characterized by the above-mentioned. And its manufacturing method. Conventionally, agar has been used as a food, but was usually in a gel state, and its performance was also expressed by gel strength (indicator indicating gel hardness) and the like, and was evaluated as a solid. It is the gist of the present invention that the agar is heated in a water-containing liquid and then cooled while applying a shearing force to obtain a liquid without gelation. It demonstrates in detail below.

Polysaccharides used in the present invention means all carbohydrates, including oligosaccharides such as disaccharides, trisaccharides, and tetrasaccharides, to generate two or more molecules of monosaccharides by hydrolysis, and to produce naturally or naturally. Although the thing which processed the polysaccharide to produce, the thing synthesize | combined artificially, etc. are mentioned, The polysaccharide derived from a plant, especially seaweed is preferable. The polysaccharides obtained from these plants may be in the form of any one of the general polysaccharides described in, for example, "Basic of Sugar Chemistry" (Abu Kimiko, Seno Nobuko; Godansha, 1984). May be used in combination. Specific examples include agar, agarose, agalopectin, starch, amylose, amylopectin, isorikenan, laminaran, rikenan, glucan, inulin, levan, fructan, galactan, metnan, xylan, arabinan, pentozan, Alginic acid, pectinic acid, protuberic acid, chitin, colomic acid, porphyran, fucoidan, ascophyllan, carrageenan, pectin, locust bean gum, guar gum, tamarind gum, tarragum, gum arabic, Gellan gum and the like, and polysaccharides obtained from seaweed, agar, agarose, agalopectin, laminaran, fructan, galactan, pentozan, alginic acid, chitin, popyran, fucoidan, ascophyllan, carrageenan and the like. This is preferable, More preferably, it is agar, agarose, and agalopectin.

Agar (agar) is a polysaccharide contained in the cell wall matrix of various flushes, such as woodpecker and snails, and is obtained by extraction with hot water. Agar is already used in foods and the like and is widely used in foods and the like because it is high in safety since it is published in the Japanese Pharmacopoeia. In addition, agar is not a homogeneous substance and is broadly classified into agarose which does not contain a sulfate group, and agaropectin that contains a sulfate group and the like. The proportion of agarose varies depending on the type of flushing, and in agar agar, agarose accounts for about 70%.

Agarose is a straight-chain structure in which D-galactose and 3,6-anhydro-L-galactose residues are alternately repeatedly bonded by β- (1 → 4) bond and α- (1 → 3) bond as shown in Formula 1 Agalopectin is an acid containing a sulfuric acid group (Formula 2), methoxyl group (Formula 3), pyruvic acid residues (Formula 4) and D-glucuronic acid (Formula 5) in various proportions in the basic skeleton of the agarose It is a mixture of polysaccharides.

Moreover, when using agar, although it may be by any manufacturing method, it is preferable to use agar by an industrial manufacturing method from a viewpoint of stable supply. The weight average molecular weight of the agar to be used is preferably 5000 to 1.2 million, more preferably 30,000 to 800,000, still more preferably 5 to 500,000. By using these ranges, it is possible to obtain a good fluidity and excellent handling. In particular, when used as a base for medicines, the preparations can take various forms such as dropping and spraying, and further excellent ones can be obtained by oil-retaining properties such as drugs which are one of the objects of the present invention.

The polysaccharide-containing composition disclosed in the present invention includes aspects such as a mixture of a polysaccharide and a solvent such as water, a solvent such as polysaccharide and water, and a mixture of a component other than the solvent.

The concentration of the polysaccharide used in the present invention is 0.1 to 30% by weight. In the case of edible use, the higher the agar concentration, the higher the effect of improving bowel movement. Moreover, when polysaccharide is used as a base other than edible, the oil-retaining property of functional agents, such as a medicine, is acquired, and there exists a tendency for the effect to become so high that it contains many. The minimum of content of a polysaccharide becomes like this. Preferably it is 0.2 weight% or more, More preferably, it is 0.3 weight% or more, More preferably, it is 0.5 weight% or more. The upper limit is not particularly limited as long as there is no obstacle to the handleability of the final product, but it is preferably 30% by weight or less, more preferably 10% by weight or less, still more preferably 5% by weight or less, and most preferably 1.5% by weight. It is as follows. When agar is used as a polysaccharide, it depends on the agar used. However, if the concentration is too high, it gels, and the viscosity may exceed 700 mPa · s under the condition of 20 ° C. and 60 rpm by a B-type viscometer, so that the weight is 5 weight. % Or less is preferable.

Illustrating agar which is preferably used in the present invention, Inakushin Co., Ltd. UP-6, UP-16, UP-37, M-7, M-9, AX-30, AX-100, AX-200, BX-30, BX-100, BX-200, PS-5, PS-6, PS-7, PS-8, etc. are mentioned. These agars may be used alone, or may be used by mixing two or more kinds of agars.

The viscosity measured under conditions of 20 ° C. and 60 rpm with a type B viscometer of the polysaccharide-containing composition according to the present invention is 700 mPa · s or less, preferably 500 mPa · s or less, more preferably 150 mPa · s or less, most Preferably it is 100 mPa * s or less. The lower limit of the viscosity is not particularly limited, but considering the practicality, it is about 1 mPa · s.

Polysaccharides such as conventional agar have been used to utilize gel properties, so they are obviously used in an amount of 0.1% by weight or more, and when heated in an aqueous medium and then cooled to room temperature, gels, and naturally a very high viscosity is expressed. In particular, at 0.1 wt% or more, in most cases, it is gelled, and at 0.3 wt% or more, it is completely gelled to obtain 700 mPa · s or less. Although the polysaccharide containing composition of this invention has such a characteristic characteristic, it can be obtained by the method as mentioned later, for example.

On the other hand, although the range of the optimum viscosity seen from the point of use varies depending on the use, the viscosity at the time of storage is preferably 200 mPa · s or less, more preferably 150 mPa · s or less, and even more preferably 100 mPa. It is preferable to adjust so that it may be s or less (The value of the viscosity shown here is a thing measured at 20 degreeC and rotation speed 60rpm using a Brookfield viscometer). Moreover, when used for ointment etc., even if it is larger than 700 mPa * s, it can use once, but since hygiene falls, it is not preferable.

The polysaccharide-containing composition of the present invention preferably comprises an aqueous medium as one component thereof. An aqueous medium is a liquid substance which has water as a main component, and components other than water are not specifically limited, It is preferable that the content rate of water exceeds 80 weight%, and it is more preferable that it exceeds 90 weight%.

The aqueous medium preferably contains a water soluble compound. Such water-soluble compounds are not particularly limited as long as they dissolve in water to provide a stable composition. Examples thereof include alcohols such as methanol, ethanol, ethylene glycol, propylene glycol and glycerin, various surfactants, emulsifiers, dispersants, and isotonic agents. In addition to the above low molecular weight compounds, water-soluble high molecular compounds such as polyethylene glycol and polyvinyl alcohol can also be used. These water-soluble compounds may be used alone or in combination of two or more thereof.

In the polysaccharide-containing composition of the present invention, a part or all of the polysaccharides may form a particulate gel. The aspect in which a part of polysaccharide forms the gel of particulate form is preferable. Moreover, it is preferable that this particulate gel is uniformly dispersed.

In the case where the fine gel is formed, the shape of the gel is not particularly limited, and examples thereof include spherical, elliptic or irregular shapes. It is preferable that it is spherical because no foreign matter is provided, and the diameter of the fine particles is preferably 100 µm or less, more preferably 50 µm or less, still more preferably 20 µm or less, and most preferably 10 µm or less. When the microparticle diameter is too large, it may adversely affect the storage stability of the composition, or when it is used, for example, in eye drops, etc., there may be a problem in terms of function, such as a feeling of foreign matter after eye drops.

Next, the method of obtaining the polysaccharide containing composition of this invention is concretely mentioned and demonstrated.

First, a predetermined amount of polysaccharide and an aqueous medium and other components are mixed as necessary, and the obtained mixture is heated to dissolve the polysaccharide. As a heating means, a conventionally well-known method can be used. Heating is carried out at a gel transition temperature or higher, preferably at a gel transition temperature of + 20 ° C. or higher. In addition, it is sometimes necessary to boil the mixture. And preferably, the liquid is in a transparent and uniform state. It is then cooled while providing stress.

The method of applying this stress is not particularly determined, such as vibration, stirring, compression, or pulverization. However, stirring is most preferable because a shear force is applied to the liquid. Specifically, a stirring device such as a magnetic stirrer, a mechanical stirrer, a mixer, a shaker, a rotor, and a homogenizer may be used or may be stirred by an attractive force.

The means for cooling may include air cooling, water cooling, ice cooling, solvent cooling, wind cooling, and the like, and conventionally known means may be used. The cooling rate may be appropriately selected depending on the properties of the polysaccharide to be used or the properties of the polysaccharide-containing composition to be obtained, but air cooling, water cooling, and ice cooling are usually performed. In the case of rapidly cooling by water cooling, ice cooling or the like, it is necessary to increase the agitation force so that gelation does not occur. Cooling is sufficient in principle if cooled below the gel transition temperature, but in practice, the gel transition temperature is -20 ° C or lower, or the polysaccharide-containing composition of the present invention is about 20 ° C because its use is usually performed at room temperature. Cool to Moreover, it is preferable to continue stirring for 10 minutes or more so that gelatinization does not occur after the temperature of a composition reaches the target temperature.

In addition, when stirring, although the viscosity of a polysaccharide containing composition increases with temperature fall, it is necessary to stir and resist this viscosity. It is preferable to use a powerful means as the stirring means. Specifically, it is preferable to stir while adjusting the Reynolds number of the stirring to be 100 or more at room temperature.

In addition, when a stirring method having a relatively small shearing force such as a magnetic stirrer or a mechanical stirrer is used as the stirring means, as disclosed in the above-mentioned known documents of the Journal of Biological Macromolecules, 26 (1999), p 255-261, FIG. 8. The higher the shear force (shear rate), the lower the viscosity of the composition is obtained, but as described in detail in the Examples described later, shear force (shear rate) such as a homogenizer (e.g., TK HOMO MIXER manufactured by Tokushu Kagyo Kogyo Co., Ltd.). It is preferable to shear using a shearing force belonging to the region of the shearing force in which the viscosity of the product becomes higher when a higher shearing force is applied using a means for applying a large stress. By using such a method, the number of gel particles can be reduced or the particle size thereof can be reduced, and the effect can be more effectively exhibited when the eye drop feeling when used as a component of an eye drop is excellent or when used with a functional agent.

In this invention, a polysaccharide containing composition is manufactured so that it may become 700 mPa * s or less in viscosity measured on 20 degreeC and 60 rpm conditions using the Brookfield viscometer (rotor No.2). Adjustment of such viscosity is performed combining a stress application means, stress application conditions, etc. according to the kind and concentration of polysaccharide to be used. These are specifically illustrated in Examples and the like.

Although the low viscosity and high concentration agar containing composition can be manufactured by the above-mentioned method, although the principle cannot be made clear, it can think as follows. The gelation of agar is considered to be because chains of agar molecules form hydrogen bonds between molecular chains, take a spiral structure while incorporating water molecules, and take a stronger structure in a higher dimension. When heated to high temperature and uniform, it tries to take a spiral structure as the agar molecule, which has a molecular structure on a random coil, cools, but prevents taking a spiral structure by applying a strong shear force to it, and does not gel, It is thought that a liquid composition can be obtained.

An isotonicity agent preferably used in the present invention is generally a solute contained in an isotonic solution. An isotonic solution is an addition of an isotonic agent so that the penetration pressure is the same for one solution when there are two or more solutions having different penetration pressures. Isotonic agents can be used when the compositions are used alone or in combination with a plurality of compositions in the present invention. The addition amount of the isotonic agent is not particularly limited as long as it is for adjusting to any penetration pressure. Examples of such isotonic agents include glycerin, propylene glycol, sorbitol, mannitol, sodium chloride, sodium phosphate, boric acid, borax, and the like.

Moreover, the composition of this invention contains a polysaccharide and a water-soluble compound at least, and has a preferable viscosity characteristic as a thickening rate represented by a following formula, and exhibits a preferable function in combined use with a pharmaceutical use or other functional agents. This thickening rate X is defined by the following formula.

X = Z / Y

Here, Y is the viscosity measured on condition of 20 degreeC and 60 rpm by the B-type viscosity meter (rotor No. 2) of the polysaccharide containing composition containing a water-soluble compound, Z is a polysaccharide containing composition containing the said isotonic agent and a water-soluble compound. It is the viscosity measured on condition of 20 degreeC and 60 rpm by B-type viscosity meter (rotor No. 2) after adding 0.9 weight% of NaCl to the.

When the thickening rate X is 1.005 or more, the composition of the present invention exhibits characteristics such as difficulty in flowing down due to thickening or long-term retention in the coating part when the composition of the present invention comes into contact with a physiological liquid containing a salt such as sweat or tear fluid. . In order to further exhibit such a characteristic, it is preferable that the thickening rate X is 1.008 or more, More preferably, it is 1.010 or more. However, when thickening rate X exceeds 3.000, since the thickening of the viscosity after application | coating is too rapid, when it is applied to cosmetics etc., a sense of incongruity may arise.

The use of the composition in the present invention includes, but is not limited to, medicines used for humans or animals, bases for medicines, foods, cosmetics, bathroom products, and the like. Specifically, foods with a taste in the oral cavity, sunscreen creams that are difficult to flow into seawater, cosmetics that cannot be removed by sweat, medical ointments that do not flow into sweat, and eye drops that suppress the leakage of the active ingredient due to leakage. Can be mentioned.

For example, when the composition of the present invention is used as a component of the ear drops, the active drug in the ear drops can be used both as soluble in water and insoluble in water. In the case of using a drug insoluble in water, a water-soluble compound such as ethanol, isopropanol, propylene glycol, glycerin, a surfactant, or the like can be suitably used as another component.

Illustrative active drugs to be applied to the present invention include, for example, hypnotic sedatives such as glutetidem, chloral hydrate, nitrazepam, amobarbital and phenobarbital; Antipyretic analgesic anti-inflammatory agents such as aspirin, acetoaminophen, ibuprofen, flubiprofen, indomethacin, ketoprofen, diclofenac sodium, tiaramid hydrochloride, pyricampam, flufenamic acid, mefenamic acid, pentazocin, etc .; Local anesthetics such as methyl aminobenzoate and lidocaine; Topical vasoconstrictors such as napazoline nitrate, tetrazoline nitrate, oxymethazolin hydrochloride, and tramazoline hydrochloride; Anti-allergic agents such as maleic acid chlorpheniramine, sodium chromoglycinate, oxatomid, azelastine hydrochloride, ketothifen fumarate, sodium traxanox, and Amlexanox; Fungicides such as benzethonium chloride, strong cores such as dopamine hydrochloride and ubidecarenone; Arrhythmia solvents such as propranolol, pindolol, phenytoin, and disopyramid; Coronary vasodilators such as isosorbate nitrate, nifedipine, diltiazem hydrochloride and dipyridamole; Digestive system solvents such as domperidone; Adrenal cortex hormones such as triamcinolone acetonide, dexamethasone, sodium betamethasone phosphate, prednisolone acetate, fluorinide, beclomethasone propionate and flunisolid; Antiplasmin agents such as tranexamic acid; Antifungal agents such as clotrimazole, myconazole nitrate and ketoconazole; Anti-malignant tumor agents, such as tegapur, fluorouracil, and mercaptopurine; Antibiotics such as amoxicillin, ampicillin, cephalexin, cepharotin sodium, ceftioxime sodium, erythromycin, and oxytetracycline hydrochloride; Physiologically active peptides such as calcitonins such as insulin, salmon calcitonin, chicken calcitonin, and elcatonin, urokinase, TPA, interferon; Vaccines such as influenza vaccine, swine bodetella infection prevention vaccine, hepatitis B vaccine and the like. The amount of active drug varies depending on the type of drug, but is generally formulated in an amount sufficient to exert the desired drug.

The example of the chemical agent which can be applied to the skin of the mammal applied to this invention is shown below. Parasitic skin disease solvents include biponazole, saccanine, bisdecalinium acetate, clotrimazole and salicylic acid, and the purulent disease solvents include sulfamethoxazole sodium, erythromycin and gentamicin sulfate. Examples of anti-inflammatory analgesic agents include indomethacin, ketopropene, betamethasone valeric acid and fluorinone acetonide, and the like as a stimulant, diphenhydramine, etc., and local anesthetics include procaine hydrochloride and Lidocaine hydrochloride etc. are mentioned, As a disinfectant disinfectant for skin, iodine, povidone iodine, benzalkonium chloride, chlorhexidine gluconate, etc. are mentioned.

Examples of drugs that can be applied to the body cavity of a mammal applied to the present invention, namely, the rectum, urethra, nasal cavity, vagina, ear canal, oral cavity or oral cavity, are shown below. Examples of the antihistamine include diphenhydramine hydrochloride and chlorpheniramine maleate, and the reproductive organ solvents include clotrimazole, napazoline nitrate, ketotifen fumarate and myconazole nitrate. Tetrizoline, etc., Aminophylline etc. are mentioned as a bronchodilator, Fluorouracin etc. are mentioned as a metabolic antagonist, Diazepam etc. are mentioned as a hypnotic sedative, Aspirin is an antipyretic analgesic anti-inflammatory agent , Indomethacin, slyndak, phenylbutazone and ibuprofen, and the adrenal hormones include dexamethasone, triamcinolone, hydrocortisone, and the like. As local anesthetics, there may be mentioned lidocaine hydrochloride, etc. Zero may include sulfisoxazole kanamycin, tobramycin, and erythromycin. Synthetic antibacterial agents include nofloxacin and nalidic acid. Can be mentioned.

Although the content of the effective drug varies depending on the type of drug, it is generally preferable to be in the range of about 0.001 to 10% by weight.

As a pH adjuster used for the composition of this invention, acids, such as hydrochloric acid, a sulfuric acid, a boric acid, phosphoric acid, an acetic acid, bases, such as sodium hydroxide, monoethanolamine, diethanolamine, a triethanolamine, are mentioned.

The composition of the present invention may include pharmaceutically acceptable buffers, salts, preservatives and solubilizing agents and the like as necessary. Preservatives include reverse soaps such as benzalkonium chloride, benzetonium chloride and chlorhexidine gluconate, parabens such as methyl paraben, ethyl paraben, propyl paraben and butyl paraben, alcohols such as chlorobutanol, phenylethyl alcohol and benzyl alcohol, Organic acids such as sodium dihydroacetic acid, sorbic acid and sodium sorbate, salts thereof and the like can be used. Moreover, surfactant and a chelating agent can also be added suitably. Such components are generally used in the range of about O.OO1 to 2% by weight, preferably about 0.002 to 1% by weight. Examples of the buffer include alkali metal salts of acids such as phosphoric acid, boric acid, acetic acid, tartaric acid, lactic acid and carbonic acid, glutamic acid, epsilonaminocaproic acid, aspartic acid, glycyl, arginine and lysine, amino acids such as taurine, trisaminomethane, and the like. Can be. These buffers are preferably added to the composition in an amount necessary to maintain the pH of the composition at 3-10.

Examples of the solubilizer include polysorbate 80, polyoxyethylene cured castor oil, cyclodextrin, and the like, and in the case of using them, the solubilizer is preferably used in the range of 0.001 to 15% by weight.

2nd invention is the "eye drop which improved the intraocular performance of a drug by mix | blending agar." In particular, when a particulate agar is used as a base for eye drops, eye drops having excellent characteristics can be obtained. In addition, the present invention is an "information performance enhancing agent for drugs, which is characterized by using agar as a base".

Agar is already used in foods and the like and can be easily obtained from seaweeds such as woodworms. The main components of agar are polysaccharides composed of agarose and agalopectin, and have high safety even from those listed in the Japanese Pharmacopoeia, and are widely used in foods and the like. In addition, agar can be processed to have desired properties, and it is relatively easy to modify it physically or chemically. Although commercially available agar contains 10 to 30% of moisture, the eye drop of the present invention may use commercially available agar as it is, or may use physically or chemically modified agar.

Although the agar used for the eye drop of this invention may be by all manufacturing methods, it is preferable to use agar by an industrial manufacturing method from a viewpoint of stable supply. As such agar, for example, UP-6, UP-16, UP-37, M-7, M-9, AX-30, AX-100, AX-200, BX-30, made by Inasho Kogyo Co., Ltd., BX-100, BX-200, PS-5, PS-6, PS-7, PS-8, etc. are mentioned. The agar used in the present invention may be used alone or in combination of two or more thereof.

Although the molecular weight of the agar contained in the eye drop of this invention is not specifically limited, It is preferable that the weight average molecular weights are 5000-1,200,000. More preferable weight average molecular weights are 30,000-800,000. This is because when the weight average molecular weight of the agar is less than 5000, the intraocular transition performance of the drug does not improve so much, and when the other weight average molecular weight exceeds 1.2 million, it becomes difficult to maintain the viscosity of the eye drop at 150 mPa · s or less. The weight average molecular weight of agar can be measured using a gel permeation chromatograph.

Although content of the agar in the eye drop of this invention is not specifically limited, It is preferable that it is 0.1-10 weight%. More preferable content of agar is 0.2 to 5% by weight. This is because when the content of the agar is less than 0.1% by weight, the intraocular transition performance of the drug does not improve so much, and when the content of the agar exceeds 10% by weight, the eye drop may be gelated due to high viscosity.

It is preferable to adjust the viscosity of the eye drop of this invention to 150 mPa * s (= 150 centipoise) or less with an E-type viscosity meter (25 degreeC, shear rate: 100s- ¹ ) from a viewpoint of the ease of eyedrops. The viscosity of a more preferable eye drop is 100 mPa * s or less. If the viscosity at the time of eye drops exceeds 150 mPa · s, eye drops as droplets become difficult. Even if a high viscosity eye drop is applied, eye drops can be applied. However, the injection of the liquid is poor, and a dose is not constant, and a problem such as a foreign body feeling after the eye drop occurs. Moreover, although filtration sterilization is widely used as a sterilization method of eyedrops, it becomes difficult to filter when the viscosity becomes high. By setting the viscosity as described above, a stable drop of eyedropping is possible, and the user is also excellent in the feeling of instillation. The viscosity of the eye drop of this invention is measured using an E-type viscosity meter, and is a value when a shear rate is 100 s <^-1> at 25 degreeC of measurement temperature. In the case of using the eye drop of the present invention as an ointment, even if the viscosity of the ointment becomes 150 mPa · s or more, it does not matter.

The agar included in the eye drop of the present invention may contain agar of all states in a liquid whose main component is water, for example, agar may be completely dissolved, or agar may be partially dissolved. The particles may be in a dispersed state. It is preferable that the thing of the state which the particle | grains of an agar disperse | distributed is a thing in which the granular agar was disperse | distributed to water, and the particle diameter of the particulate agar is 100 micrometer or less. More preferably, it is 20 micrometers or less, and 10 micrometers or less are more preferable. If the particle diameter of the agar exceeds 100 µm, problems such as adverse effects on the storage stability of the eye drop may be caused, and foreign matters may be felt after the eye drop. The shape of the particulate agar is not particularly limited. In addition to the elliptic shape, an irregular shape may be mentioned.

The eye drop of the present invention can be prepared by, for example, mixing a solution containing particulate agar obtained by heating and dissolving agar in an aqueous solution and then cooling while applying a stress.

The method for producing the agar-containing solution (ie, the agar-containing composition) is not particularly limited, but the aqueous solution containing the agar is heated until uniform, and then cooled slowly until normal temperature while stirring vigorously to prevent gelation. Although it is preferable to make it gelatinize, gelatinized thing may be grind | pulverized by stress, such as a strong shearing force, and the liquid agar-containing solution can be obtained.

The method of applying stress to the aqueous solution of agar is not particularly limited. For example, vibration, shear, stirring, compression, or crushing may be used. Stirring is most preferred as a method of applying stress to the agar solution. As the stirring device, for example, all stirring devices such as a magnetic stirrer, a mechanical stirrer, a mixer, a stirrer, a rotor, and a homogenizer (for example, TK HOMO MIXER manufactured by Tokushu KKK) can be used. It can also be stirred. In the preparation of the agar-containing solution, it is preferable to use an apparatus having the ability to stir vigorously, and more preferably, stirring while adjusting the Reynolds number to be 100 ° C or higher even at room temperature.

The heating temperature of the agar-containing aqueous solution may be a temperature which becomes uniform when the agar-containing solution is seen in appearance, preferably 80 ° C. or more, and more preferably 95 ° C. or more. Moreover, it can also boil as needed.

The cooling method of the agar-containing solution may be any method such as air cooling, water cooling, ice cooling, solvent cooling, wind cooling, refrigeration, or freezing. However, in the case of rapid cooling by water cooling, ice cooling, refrigeration, freezing, etc., the stirring force is greatly increased so as not to gel. Needs to be.

By this method, it is possible to produce a low viscosity and high concentration agar-containing solution. Although the principle is not clear, it is guessed as follows. It is thought that agar gels because hydrogen chains form hydrogen bonds between molecular chains, take a spiral structure including water molecules, and take a stronger structure in a higher dimension. The agar molecules, which had a random coil-like molecular structure when heated to a high temperature, try to take a spiral structure as they cool, but as a result of applying a strong stress to the spiral structure, it prevents taking a spiral structure, resulting in low viscosity without gelation. It is assumed that an agar solution with phosphorus is obtained.

As an aspect of the preferable eyedrop of this invention, the eyedropper whose viscosity which mix | blended 0.1-10 weight% of agar with a weight average molecular weight of 5000-1,20 and a particle diameter of 100 micrometers or less is 150 mPa * s or less, for example is more preferable. As an aspect, the weight average molecular weight is 30,000-800,000, and the viscosity which mix | blended 0.2-5 weight% of agar whose particle diameter is 20 micrometers or less is 100 mPa * s or less eyedrops. In addition, an eye drop which improves drug guidement performance, in particular, a weight average molecular weight, by blending agar having a weight average molecular weight of 5000 to 1.2 million in an aqueous solution, followed by heating while dissolving it in an aqueous solution, and then mixing the particulate agar having a particle size of 100 μm or less. After dissolving this 30,000-800,000 agar in aqueous solution, the eyedrop which improved the intraocularly guiding property of a drug by mix | blending the particulate-form agar of 20 micrometers or less obtained by cooling under stress is preferable.

In addition, the aspect of the preferable drug | guide_information performance improvement agent of this invention uses the particulate agar obtained by heat-dissolving an agar in aqueous solution, and cooling it under stress, for example, The guide of the drug characterized by the above-mentioned. And a transition improving agent. More preferably, the drug using a particulate agar having a particle size of 100 µm or less as a base obtained by heating and dissolving an agar having a weight average molecular weight of 5000 to 1.2 million in an aqueous solution and then cooling it under stress. It is an intraocular migration improver, More preferably, after dissolving agar having a weight average molecular weight of 30,000 to 800,000 in an aqueous solution by heating and dissolving it under stress, the drug using a particulate agar having a particle size of 20 µm or less as a base is obtained. Guideline performance enhancer.

The eye drop of the present invention is not limited in terms of its target disease, and for example, it functions effectively for each disease by containing a drug suitable for the treatment of dry eye syndrome, glaucoma, cataracts, inflammation, hay fever and the like.

Although the kind of drug which can be mix | blended with the eyedrop of this invention is not specifically limited, For example, antibacterial agent (quinolone type antibacterial agent, cephalosporins, sulfaacetamide sodium, sulfamethoxazole etc.), anti-inflammatory agent (hydrocortisone, dexamethasone, etc.). Prednisolone, betamethasone, diclofenac, indomethacin, fluorometholone, pranopropene, dipotassium glycyrrhinate, epsilon-aminocaproic acid, etc., antihistamines (such as chlorpheniramine maleic acid, diphenhydramine hydrochloride, etc.), antiglaucoma agents (Prostaglandin derivatives, carbonic anhydrase inhibitors, etc.), anti-allergic agents (sodium chromoglycine sodium, etc.), etc. are mentioned.

Examples of immunosuppressants and metabolic antagonists include methotrexate, cyclophosphamide, cyclosporine, 6-mercaptopurine, azathiopurine, fluorouracil and tegapur, and also mixtures of the above compounds, eg For example, a mixture such as an antibiotic / anti-inflammatory mixture such as a combination of neomycin sulfate and sodium dexamemethasone phosphate may be used, but other agents may be used for the treatment of eye symptoms and lesions.

Although it is preferable that the addition amount of a drug is 0.001 to 10 weight%, it will not specifically limit, if it is a density | concentration which a therapeutic effect expresses.

The eye drop of the present invention can be suitably blended with isotonic agents, buffers, pH adjusting agents, solubilizers, stabilizers, preservatives and the like as other additives in addition to the above components.

Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, and the like.

Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, ε-aminocaproic acid, tromethamol and the like.

Examples of the pH regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogencarbonate, and the like.

Examples of the solubilizer added to the drug or other additives in poor water solubility include polysorbate 80, polyoxyethylene hardened castor oil 60, macrogol 4000 and the like.

As a stabilizer, edetic acid, sodium edate, etc. are mentioned, for example.

Examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzogenium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. These preservatives may be used in combination.

The eye drop of this invention can be manufactured by adding agar and a drug to sterile purified water, and can also adjust to target viscosity by performing high speed stirring, ultrasonic irradiation, etc. as needed.

In the test examples described later, fluorescein and pilocarpine were used as indicators for measuring the amount of intraocular shift, and the pupil diameter by fluorescence or pilocarpine of fluorescein transferred during cornea or waterproofing was measured. Although the detailed result is described in the term of the Example, when using the microparticle-like agar of this invention as a base | substrate, the guidance | transformation performance which was especially excellent compared with the control group was confirmed. As is evident from these test examples, the drug-induced adherence can be improved by using the particulate agar as a base for eye drops.

It is preferable to set the pH of the eye drop of this invention to 4.0-8.0, and it is preferable to set the penetration ratio to around 1.0.

The number of eye drops of the eye drop of the present invention can be appropriately selected depending on symptoms, age, formulation, and the like, but may be administered once to several times per day.

Claims (44)

The polysaccharide containing composition containing 0.1-30 weight% polysaccharides, and the viscosity measured on the conditions of 20 degreeC and 60 rpm with the Brookfield viscometer (rotor No. 2) is 700 mPa * s or less. The polysaccharide-containing composition according to claim 1, wherein the viscosity measured under a condition of 20 ° C. and 60 rpm with a type B viscometer (rotor No. 2) is 500 mPa · s or less. The polysaccharide-containing composition according to claim 1 or 2, wherein the polysaccharide content is 0.2 to 10% by weight. The polysaccharide-containing composition according to any one of claims 1 to 3, comprising a polysaccharide and an aqueous medium, wherein the aqueous medium consists of water and a water-soluble compound. The polysaccharide-containing composition according to claim 4, wherein the water-soluble compound is a polyhydric alcohol. Contains at least a polysaccharide and a water-soluble compound, The polysaccharide-containing composition, wherein the thickening rate X represented by the following formula is 1.005 or more. X = Z / Y Here, Y is the viscosity measured on condition of 20 degreeC and 60 rpm by the B-type viscosity meter (rotor No. 2) of the polysaccharide containing composition containing a water-soluble compound, and Z adds 0.9 weight% of NaCl to this polysaccharide containing composition. The viscosity measured on 20 degreeC and 60 rpm conditions with the B-type viscosity meter (rotor No. 2) after that. The polysaccharide-containing composition according to claim 6, wherein the thickening ratio X is 1.008 or more. 7. The polysaccharide-containing composition according to claim 6, wherein the thickening ratio X is 1.010 or more. The polysaccharide-containing composition according to any one of claims 1 to 8, wherein the polysaccharide is in particulate form, and all or part of the particulate polysaccharide is dispersed in an aqueous solution. The polysaccharide-containing composition according to claim 9, wherein the particle diameter of the particulate polysaccharide is 100 μm or less. The polysaccharide-containing composition according to claim 9, wherein the particle diameter of the particulate polysaccharide is 20 μm or less. The polysaccharide-containing composition according to any one of claims 1 to 11, which contains a polysaccharide obtained from a plant. 13. The polysaccharide-containing composition according to claim 12, wherein the polysaccharide obtained from the plant is agar. The polysaccharide-containing composition according to claim 13, wherein the weight average molecular weight of the agar is 50 to 1.2 million. The polysaccharide-containing composition according to claim 13, wherein the weight average molecular weight of the agar is 30,000 to 800,000. The polysaccharide-containing composition according to any one of claims 1 to 15, wherein an isotonicity agent is included. The base for pharmaceutical products using the polysaccharide containing composition of any one of Claims 1-16. A pharmaceutical comprising the polysaccharide-containing composition according to any one of claims 1 to 16. An intraocular performance improver, comprising the polysaccharide-containing composition according to any one of claims 1 to 16. Food containing the polysaccharide containing composition of any one of Claims 1-16. Cosmetics containing the polysaccharide containing composition of any one of Claims 1-16. As a method for producing a polysaccharide-containing composition obtained by dissolving a composition comprising 0.1 to 30% by weight of a polysaccharide and an aqueous medium at or above the gel transition temperature of the polysaccharide, and cooling it below the gel transition temperature while applying a shear force to the composition. The viscosity measured on condition of 20 degreeC and 60 rpm using the Brookfield viscometer (rotor No. 2) of the obtained composition is 700 mPa * s or less, The manufacturing method of the polysaccharide containing composition characterized by the above-mentioned. The method for producing a polysaccharide-containing composition according to claim 22, wherein the shearing force according to claim 22 is selected in a shearing force region in which the viscosity of the preparation becomes higher when higher shearing force is applied. Eye drops that improve the intraocular performance of the drug by blending agar. The eye drop according to claim 24, wherein the weight average molecular weight of the agar is 50 to 1.2 million. The eye drop according to claim 24, wherein the weight average molecular weight of the agar is 30,000 to 800,000. The eye drop according to claim 24, wherein the content of agar is 0.1 to 10% by weight. The eye drop according to claim 24, wherein the content of agar is 0.2 to 5% by weight. The eye drop according to claim 24, wherein the viscosity of the eye drop is 150 mPa · s or less with an E-type viscometer (25 ° C., shear rate: 100 s ⁻¹ ). The eye drop according to claim 24, wherein the viscosity of the eye drop is 100 mPa · s or less with an E-type viscometer (25 ° C., shear rate: 100 s ⁻¹ ). The eye drop according to claim 24, wherein the agar is in particulate form having a particle size of 100 µm or less. The eye drop according to claim 24, wherein the agar is in particulate form having a particle diameter of 20 µm or less. The viscosity measured by E type | mold viscosity meter (25 degreeC, shear rate: 100s- ¹ ) by mix | blending 0.1-10 weight% of agars with a weight average molecular weights of 5000-1,200,000 and a particle diameter of 100 micrometers or less is 150 mPa * s Eye drops that are below. The viscosity measured by E type | mold viscosity meter (25 degreeC, shear rate: 100s- ¹ ) by mix | blending 0.2-5 weight% of agars with a weight average molecular weights of 30,000-800,000 and a particle diameter of 20 micrometers or less is 100 mPa * s Eye drops that are below. The eye drop which improved the guide-transformation property of a drug by mix | blending the particulate agar obtained by heat-dissolving agar in aqueous solution and cooling under stress. The eye drop according to claim 35, wherein the weight average molecular weight of the agar is 5000 to 1.2 million, and the particle size of the particulate agar is 100 m or less. The eye drop according to claim 35, wherein the weight average molecular weight of the agar is 30,000 to 800,000, and the particle size of the particulate agar is 20 µm or less. A method for improving intraocular performance of a drug incorporating agar in eye drops. An agent for improving intraocular performance of a drug, which uses agar as a base. A fine particle agar obtained by heating and dissolving agar in an aqueous solution and then cooling with stress is used as a base agent. 41. The drug-information-improving agent according to claim 40, wherein the weight average molecular weight of the agar is 5000 to 1.2 million and the particle size of the particulate agar is 100 m or less. 41. The drug-information-improving agent according to claim 40, wherein the weight average molecular weight of the agar is 30,000 to 800,000 and the particle size of the particulate agar is 20 m or less. A method for improving intraocular performance of a drug based on agar. A method for treating ocular disease, comprising administering to a patient an effective amount of an eye drop containing agar.